Colorectal polyps and cancer: Pathology review

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Case Study0:00–0:37

At the gastroenterology clinic, there is a 63-year-old Caucasian male, named Neil, who's complaining about progressive fatigue and weight loss in the last 6 months.
Laboratory findings reveal positive fecal occult blood test and iron-deficiency anemia. At the same time, an 18-year-old Caucasian male, named Brendon came in for a colonoscopy screening.
He was concerned after learning that both his grandfather and uncle were diagnosed with colon cancer in their early thirties.
His doctor detected more than one hundred polyps on colonoscopy.Now, both people have some form of colorectal polyps or cancer.

Non-Neoplastic Polyps0:37–2:11

But first let’s start with colorectal polyps, which are overgrowths of epithelial cells in the colon or rectum. They are subdivided into non-neoplastic polyps, such as hamartomatous polyps, hyperplastic polyps, inflammatory pseudopolyps, mucosal, and submucosal polyps; and neoplastic polyps, which include adenomatous and serrated polyps.
Hamartomatous polyps are solitary, disorganized masses that contain normal tissue found at the site of the polyp. These polyps can occur sporadically, or in genetically inherited conditions, such as juvenile polyposis syndrome or Peutz-Jeghers syndrome; and they have mild malignant potential.
Next, hyperplastic polyps, are the most common polyps and they are small and typically located in the rectosigmoid region.
Usually, these polyps are benign lesions, but in rare cases, they can evolve into serrated polyps, which have malignant potential.
Inflammatory pseudopolyps are multiple benign pseudopolyps that occur during regenerative and healing phases in chronic inflammation, and they are most commonly seen in inflammatory bowel disease.
Mucosal polyps, which are clinically insignificant, are usually small, less than 5mm, and they look similar to surrounding normal mucosa.
On the flip side, submucosal polyps can include lipomas, leiomyomas, fibromas, or other lesions. Now let’s switch focus to neoplastic polyps!

Neoplastic Polyps2:11–4:20

Adenomatous polyps are caused by a mutation in the tumor suppressor gene called adenomatous polyposis coli or APC for short, which is located on chromosome 5 and is responsible for the regulation of cell growth and cell adhesion.
Moreover, the mutation of the APC gene is present in all familial polyposis syndromes and most cases of sporadic colon cancer.
Now let’s focus on adenoma-carcinoma sequence which includes three steps. The first step is the mutation of one allele of the APC gene, which leads to the formation of a small polyp, also called early adenoma.
The second step occurs when the small polyp acquires mutation of protooncogene called KRAS, which is further followed by an increase in the size of adenoma and formation of the late adenoma.
Finally, the third step requires mutation of tumor suppressor genes p53 and DCC. Now, adenomatous polyps less than 1cm, are less likely to acquire these mutations and undergo malignant transformation, in contrast to adenomatous polyps greater than 4cm which are more likely to progress to adenocarcinoma.
Furthermore, based on histological appearance, there are three types of adenomatous polyps: villous, which are cauliflower-like polyps that have the highest malignant potential; tubular, which are pedunculated polyps that protrude out in the lumen of the intestine, they have the lowest malignant potential; and tubulovillous, which have characteristics of both, tubular and villous polyps, and they have an intermediate malignant potential.
Usually, adenomatous polyps are asymptomatic, but in some cases, villous polyps can cause bleeding, secretory diarrhea, and partial intestinal obstruction.
Finally, serrated polyps are often flat or sessile and are characterized by saw-tooth appearance under the microscope. They contain methylated CpG islands in their genes.
DNA methylation regulates gene expression, which can cause silencing of DNA-repair genes, eventually leading to more mutations and malignancy.
After polyps, let’s look at colorectal cancer which is the third most common cancer worldwide. Most commonly it affects people older than 50 years old, and in 25% of the cases, there's a positive family history.

Colorectal Cancer4:20–7:02

Risk factors for colorectal cancer include hereditary factors, such as familial adenomatous polyposis; adenomatous and serrated polyps; inflammatory bowel disease, such as ulcerative colitis; lifestyle factors, such as obesity, smoking, alcohol, and physical inactivity; and finally, dietary factors, which include high consumption of processed red meat and low consumption of fruits and vegetables.
Individuals with acromegaly, a condition where the pituitary gland produces too much growth hormone, are at higher risk of developing colorectal cancer.
And finally, increased cyclooxygenase-2 activity is linked to some forms of colon adenocarcinoma, so frequent use of inhibitors of this enzyme like aspirin can lower risks.
For your exam, you should remember that the most common form of colorectal cancer is adenocarcinoma and it’s most commonly located in the rectosigmoid, then ascending colon, and rarely in descending colon.
Initially, adenocarcinoma can be asymptomatic but as they grow, their location determines their manifestations. Left-sided colon tumors are usually smaller, but as they infiltrate the wall of the colon, they encircle the lumen, eventually narrowing the lumen and causing obstruction.
A frequently tested concept is what is the presentation of an individual with left-sided colorectal cancer; therefore it’s important to know that these individuals present with obstruction and altered bowel habits, such as narrowing of stool, colicky pains, constipation, abdominal distension, but also hematochezia, nausea, and vomiting.
On the other hand, right-sided colon cancers grow as exophytic masses but they don’t tend to cause colon obstruction, because the right-sided colon has a larger diameter than the left.
Instead, right-sided tumors tend to cause chronic bleeding, eventually causing iron-deficiency anemia. Moreover, keep in mind that colorectal cancer is the most common cause of iron-deficiency anemia in postmenopausal women or men aged 50 or older.
Other manifestations of right-sided colon cancers include progressive fatigue, malaise, and weight loss. Common complications of colorectal cancer include local and distant metastasis, but also bowel perforation and peritonitis.
Non-enterococcal group D streptococci, Streptococcus bovis, can also cause bacteremia and subacute endocarditis. Now as far as screening goes, you should screen average-risk individuals at the age of 45; while individuals with a first-degree relative who has colon cancer, at the age of 40 or 10 years prior to their relative’s diagnosis.

Screening7:02–7:44

Screening includes visualization methods, such as colonoscopy and flexible sigmoidoscopy; and laboratory findings, such as fecal occult blood test, which is further subdivided into guaiac fecal occult blood test, or FOBT, and fecal immunochemical test, or short FIT.
On the other hand, individuals with hereditary polyposis syndromes or inflammatory bowel disease have different guidelines for screening like earlier and more frequent colonoscopies.Now, diagnosis of colorectal cancer, just like screening of colorectal cancer, includes visualization methods, such as colonoscopy and flexible sigmoidoscopy; but it also includes imaging methods, such as CT colonography and barium enema x-ray, which might show “apple core” lesions.

Diagnosis7:44–8:08

But don’t forget, diagnosis is confirmed with biopsy! As far as treatment goes, colorectal cancer can be treated with surgical resection of the colon, colectomy, and chemotherapy.

Treatment8:08–9:08

What you have to know for your exam is that serum carcinoembryonic antigen levels, or CEA levels are increased in 60-90% of individuals with colon cancer.
But, the CEA level is not specific for colon cancer only, it’s also increased in pancreatic, gastric, breast malignancies, as well as in inflammatory bowel disease, cirrhosis, and pancreatitis; therefore it can be only used to monitor the recurrence of colorectal cancer.
Moreover, if a routine check shows that CEA level is rising again after surgery, these individuals should undergo additional diagnostic methods, such as X-ray, CT, colonoscopy, to search for possible cancer recurrence or metastases.
Finally, you should remember that aspirin and other NSAIDs can be chemopreventive in colonic adenocarcinoma because colonic adenocarcinoma is associated with increased activity of an enzyme called cyclooxygenase-2.

Lynch Syndrome9:08–10:13

Okay, now that we’ve covered the basics of colorectal polyps and cancer, let’s look at some important genetic disorders that are associated with them.
First we have Lynch syndrome, previously known as hereditary nonpolyposis colorectal cancer. It’s caused by an autosomal dominant mutation in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6, or PMS2, with subsequent microsatellite instability.
Individuals with Lynch syndrome have inherited a mutation in one allele of the gene; while mutation of the second allele occurs during adult life.
Mutation of both alleles leads to colonic adenocarcinoma. For your exam, you should remember that in contrast to sporadic colonic adenocarcinoma, which is usually left-sided and occurs in individuals older than 50 years of age; in Lynch syndrome colon cancer is usually right-sided and it occurs in adults under 50 years of age.
Lynch syndrome is also associated with extraintestinal malignancies, such as endometrial, ovarian, stomach, and skin cancers.
Next, we have familial adenomatous polyposis or short FAP. This is a pancolonic condition involving hundreds to thousands of polyps and it always affects the rectum.

FAP10:13–12:02

For your exam, you need to know that this is an autosomal dominant inherited condition caused by a mutation in the tumor suppressor gene on chromosome 5q22 called APC gene.
Polyps usually begin to develop during puberty and initially, they are asymptomatic, but as they grow they can present with colonic manifestations such as palpable abdominal mass, abdominal pain, diarrhea, and hematochezia.
Moreover, chronic gastrointestinal bleeding from many polyps can lead to iron-deficiency anemia, even in children. Familial adenomatous polyposis can be also associated with extracolonic manifestations, such as congenital hypertrophy of retinal pigment epithelium, sessile polyps in the stomach called fundic gland polyps, and duodenal adenomas.Some individuals develop attenuated familial adenomatous polyposis or AFAP, and they end up with fewer than 100 polyps, typically in the ascending colon.
Now, what you absolutely need to know for your exam is that, if left untreated polyps from FAP and AFAP can progress to colorectal cancer via two-hit hypothesis.
The first step is the inherited APC mutation; while the second step is the mutation of the second allele which occurs as the polyps grow.
The favored diagnostic method for diagnosing familial adenomatous polyposis is a colonoscopy, followed by genetic testing.
For your tests, remember that individuals with a positive family history should start regular screening at 10 years of age.
Screening includes colonoscopy once a year, and if polyps are found, treatment includes prophylactic colectomy.Now, a subtype of familial adenomatous polyposis, called Gardner syndrome, is characterized by prominent extracolonic bone and soft tissue tumors, such as osteomas, fibromas, lipomas, desmoid tumors, and epidermoid cysts.

Gardner Syndrome12:02–12:29

Also, these individuals can have congenital hypertrophy of retinal pigment epithelium, supernumerary impacted teeth, and multiple jaw osteomas and odontomas.

Turcot Syndrome12:29–12:44

Next one is Turcot syndrome, which can be described as the association of familial adenomatous polyposis syndrome, or Lynch syndrome, with malignant brain tumors, like medulloblastomas or gliomas.
Next one is Peutz-Jeghers syndrome, an autosomal dominant condition caused by a mutation of the tumor suppressor STK11 gene.

Peutz-Jegher Syndrome12:44–13:19

Peutz-Jeghers Syndrome is characterized by multiple hamartomatous polyps throughout the gastrointestinal tract. These can develop into colorectal, stomach, and small bowel cancer.
Outside of the GI tract, there’s also an increased risk of developing breast cancer. It can also present with mucocutaneous hyperpigmentation macules, which are usually located on the lips, buccal mucosa, palms, soles, or genitalia.

JPS13:19–14:19

Finally, in juvenile polyposis syndrome, there are mutations in BMPR1A and SMAD4 genes, which can be inherited in an autosomal dominant manner with incomplete penetrance or they can be de novo mutations.
Typically, juvenile polyposis syndrome affects children younger than 5 years old; and these polyps can arise in any part of the gastrointestinal tract, but the majority of is found in the colon and rectum.
Children with juvenile polyposis syndrome can present with hematochezia and iron-deficiency anemia, but more importantly, they are at risk for developing colorectal cancer.
Diagnosis is made by endoscopic studies, such as endoscopy, colonoscopy, or sigmoidoscopy, and the criteria for diagnosis is more than five juvenile polyps in the colon or rectum; or multiple juvenile polyps throughout the gastrointestinal tract; or any number of juvenile polyps in a person with a family history of juvenile polyposis syndrome.

Review14:19–16:22

Diagnosis is confirmed with a biopsy.All right, as a quick recap. Colorectal polyps are overgrowths of epithelial cells in the colon or rectum and they are subdivided into non-neoplastic polyps, such as hamartomatous polyps and inflammatory pseudopolyps; and neoplastic polyps, which include adenomatous polyps and serrated polyps.
The most common form of colorectal cancer is adenocarcinoma. Left-sided colon cancers cause obstruction, narrowing of the stool, colicky pains, constipation, hematochezia, nausea, and vomiting; whereas right-sided colon cancers tend to cause malaise, fatigue, weight loss, chronic bleeding, and iron-deficiency anemia.
Genetic disorders associated with colon cancer include Lynch syndrome, a cancer syndrome associated with a high risk of colorectal cancer, endometrial, gastric, and ovarian cancer.
Familial adenomatous polyposis is an autosomal dominant pancolonic condition involving hundreds to thousands of polyps, caused by a mutation of the APC gene.
Gardner’s syndrome is a subtype of familial adenomatous polyposis characterized by prominent extracolonic bone and soft tissue tumors; while Turcot syndrome can be described as the association of Lynch syndrome with malignant brain tumors.
Peutz-Jeghers syndrome is an autosomal dominant condition caused by a mutation of the STK11 gene, and it’s characterized by multiple hamartomatous polyps throughout the gastrointestinal tract and mucocutaneous hyperpigmentation macules.
Finally, juvenile polyposis syndrome is an autosomal dominant condition that generally affects children younger than 5 years old; and these polyps can arise in any part of the gastrointestinal tract.Now let’s go back to our case.
In 63-years-old Neil, you should suspect of colon cancer because colorectal cancer is the most common cause of iron-deficiency anemia in postmenopausal women and men 50 or older.

Summary16:22–17:15

Also, positive fecal occult blood test, and non-specific symptoms such as malaise, fatigue, and weight loss, should make you think of right-sided colon cancer and order colonoscopy and biopsy to confirm the diagnosis.
Based on the severity and involvement of the colon, Neil can be treated by surgical resection of the colon, or even total removal, colectomy.
Next, Brendon has a family history of early colorectal cancer and the presence of hundreds of polyps were detected in his colonoscopy, so he was diagnosed with familial adenomatous polyposis.
He requires prophylactic colectomy because individuals with familial adenomatous polyposis are at high risk of developing colorectal cancer later in life.
So he was diagnosed with familial adenomatous polyposis. He requires prophylactic colectomy, because individuals with familial adenomatous polyposis are at high risk of developing colorectal cancer later in